The long range objective of this project is to elucidate the basic mechanisms of drug allergy in man, and to apply current and new knowledge to the development of diagnostic methods and therapeutic approaches to the clinical problems which drug hypersensitivity pose. The model system chosen for study is the most prevalent drug allergy, penicillin hypersensitivity. Our previous work supports the usefulness of skin testing with penicilloyl-polylysine and a minor determinant mixture of penicillin derivatives in predicting reactions to the drug. This finding suggests that reaginic (IgE) antibody plays a primary role in the pathogenesis of some allergic drug reactions. We have now developed an in vitro assay for penicilloyl-specific IgE antibody employing the radioallergosorbent technique (RAST), and are currently evaluating its predictive reliability as compared with direct skin testing. When sufficient sera from skin test positive patients are available, an effort will be made to develop a RAST assay for IgE antibody of minor determinant specificity. A study of the immune response of man to penicillin administration in terms of penicilloyl-specific IgE and IgG antibodies is currently underway. Preliminary results suggest that all patients respond immunologically when receiving the drug in therapeutic doses. Further efforts will investigate the influence of immunological status, dose, route and duration of therapy, and physiological variables on the induction of antipenicillin reagins.